citalopram Celexa
Cerebral activating properties of indeloxazine HCl and its optical isomers.

Shimizu-Sasamata M, Yamamoto M, Harada M.

Department of Pharmacology, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.

The cerebral activating actions of indeloxazine HCl and its optical isomers were evaluated in comparison with those of several selective monoamine uptake inhibitors. The effects of indeloxazine and its optical isomers on monoamine uptake were also determined. Indeloxazine was equipotent to the (-)-isomer in desynchronizing the spontaneous electroencephalogram (EEG) in both mature and aged rats and in accelerating recovery of consciousness induced by concussive head trauma in mice, whereas the (+)-isomer showed about 3 times less potent activity than indeloxazine and the (-)-isomer. The potency of indeloxazine and the (-)-isomer in inhibiting [14C]norepinephrine (14C-NE) uptake was approximately 25-30 times more potent than that of the (+)-isomer. Maprotiline and viloxazine, selective NE uptake inhibitors, also showed facilitatory actions in concussed mice. Selective 5-hydroxytryptamine (5-HT) uptake inhibitors such as citalopram, alaproclate, and zimeldine showed little effect. Indeloxazine, the (-)-, and the (+)-isomers facilitated passive avoidance learning behavior with a bell-shaped response curve in normal rats. The potency of the (+)-isomer in inhibiting [14C]5-HT uptake was equipotent to those of both indeloxazine and the (-)-isomer. While citalopram, alaproclate, and zimeldine also facilitated the acquisition of learning behavior, maprotiline and viloxazine, as well as the dopamine uptake inhibitor amantadine, showed little influence on the latency of step-through behavior. Amitriptyline, with anticholinergic activity, impaired learning behavior. Indeloxazine, its optical isomers, citalopram, alaproclate, and zimeldine also ameliorated cycloheximide-induced disturbance of learning behavior in mice, while maprotiline and viloxazine showed little effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8327539&dopt=Abstract citalopram Celexa



citalopram Celexa
Serotoninergic terminal transporters are differentially affected in Parkinson's disease and progressive supranuclear palsy: an autoradiographic study with [3H]citalopram.

Chinaglia G, Landwehrmeyer B, Probst A, Palacios JM.

Department of Neurochemistry, Centro de Investigacion y Desarrollo (C.S.I.C.) Jordi Girona, Barcelona, Spain.

Receptor autoradiography with [3H]citalopram as ligand was used to study the distribution of serotonin uptake binding sites in post mortem brain tissues from patients with Parkinson's disease, progressive supranuclear palsy and from age-matched controls. Significant decreases in [3H]citalopram binding sites were found in the cerebral cortex of patients with Parkinson's disease and progressive supranuclear palsy. Densities of [3H]citalopram binding sites were significantly reduced in all components of the basal ganglia of Parkinson's disease but only in the head of caudate nucleus of progressive supranuclear palsy patients. The density of [3H]citalopram binding sites in the raphe nuclei of Parkinson's disease was comparable to control values. Our results suggest that serotoninergic terminals are differentially affected in Parkinson's disease and in progressive supranuclear palsy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8332256&dopt=Abstract citalopram Celexa



citalopram Celexa
Determination of plasma levels of citalopram and its demethylated and deaminated metabolites by gas chromatography and gas chromatography-mass spectrometry.

Reymond P, Amey M, Souche A, Lambert S, Konrat H, Eap CB, Baumann P.

Unite de Biochimie et Psychopharmacologie Clinique, Departement Universitaire de Psychiatrie Adulte, Prilly-Lausanne, Switzerland.

Sensitive and specific methods based on gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) for the determination of levels of citalopram, desmethylcitalopram and didesmethylcitalopram in the plasma of patients treated with citalopram are presented, as well as a GC-MS procedure for the assay of the citalopram propionic acid derivative. After addition of a separate internal standard for each drug, liquid-solvent extraction is used to separate the basic compounds from the acid compounds. The demethylated amines are derivatized with trifluoroacetic anhydride, and the acid metabolite with methyl iodide. GC-MS is performed in the electron impact mode, as mass spectrometry by the (positive-ion) chemical ionization mode (methane and ammonia) appeared to be unsuitable. The limits of quantification were 1 ng/ml for citalopram and desmethylcitalopram and 2 ng/ml for the other metabolites. The correlation coefficients for the calibration curves (range 10-500 ng/ml) were > or = 0.999 for all compounds, whether determined by GC or GC-MS.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8376503&dopt=Abstract citalopram Celexa



citalopram Celexa
Enhancement of the responsiveness of cortical adrenergic receptors by chronic administration of the 5-hydroxytryptamine uptake inhibitor citalopram.

Nalepa I, Vetulani J.

Institute of Pharmacology, Polish Academy of Sciences, Krakow.

The aim of this study was to evaluate the effect of citalopram, a second generation antidepressant agent producing no beta-down-regulation, on the receptors and second messenger systems related to noradrenergic transmission in the cerebral cortex of the rat. We confirmed that citalopram does not bind to alpha 1-, alpha 2-, and beta 1-adrenoceptors, but we found that it attenuates the inhibitory action of the protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate, on the noradrenergic response from alpha 1-adrenoceptor. In contrast to most antidepressants, chronic treatment with citalopram does not produce beta-down-regulation, but increases the responses to noradrenaline from beta-adrenoceptors without increasing the beta 1-adrenoceptor density. Chronic treatment with citalopram also increases the maximal response from alpha 1-adrenoceptor. The results indicate that beta-down-regulation is not a necessary characteristic of an efficient antidepressant drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8388032&dopt=Abstract citalopram Celexa



citalopram Celexa
Serotonin 5-HT1A autoreceptor blockade potentiates the ability of the 5-HT reuptake inhibitor citalopram to increase nerve terminal output of 5-HT in vivo: a microdialysis study.

Hjorth S.

Department of Pharmacology, University of Goteborg, Sweden.

The present study addressed the possibility that disinhibition of serotonin (5-HT) autoreceptor-mediated negative feedback might potentiate the elevation of nerve terminal 5-HT output induced by selective 5-HT reuptake blockade. To this end, rats were given citalopram and the 5-HT autoreceptor-blocking agents (S)-UH-301 (5-HT1A) and (-)-penbutolol (5-HT1A/1B), and the effect on extracellular 5-HT in the ventral hippocampus was monitored by means of in vivo microdialysis. Citalopram (5 mg/kg, s.c.) approximately doubled the 5-HT output, a response that was markedly augmented by (S)-UH-301 (3 mg/kg, s.c.) and (-)-penbutolol (8 mg/kg, s.c.) and by combined treatment with (S)-UH-301 (3 mg/kg, s.c.) plus (-)-penbutolol (1 microM; via the dialysis perfusion medium), but not by (-)-penbutolol (1 microM) alone. These findings provide evidence that 5-HT, in particular 5-HT1A, autoreceptor-mediated negative feedback mechanisms are pivotal in determining the nerve terminal 5-HT output level after 5-HT reuptake inhibition. These findings have important implications for the interplay between different processes controlling 5-HT transmission in vivo and might possibly offer a lead toward novel, therapeutically exploitable principles.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8419553&dopt=Abstract citalopram Celexa



citalopram Celexa
Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms.

Sindrup SH, Brosen K, Hansen MG, Aaes-Jorgensen T, Overo KF, Gram LF.

Department of Clinical Pharmacology, Odense University, Denmark.

The relationship between the metabolism of the selective serotonin reuptake inhibitor citalopram and the sparteine and mephenytoin oxidation polymorphisms was studied in 24 healthy male volunteers, constituting panels of extensive metabolizers of sparteine and mephenytoin (n = 10), poor metabolizers of sparteine (n = 8), and poor metabolizers of mephenytoin (n = 6). Each subject was given 40 mg/day citalopram for 10 days and citalopram, and its des- and didesmethylmetabolites were assayed in serum and urine. Using a nonenantioselective analytical method (high-performance liquid chromatography), it was shown that the citalopram elimination partially depends on the mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for citalopram were significantly higher in poor metabolizers of mephenytoin than in extensive metabolizers of mephenytoin. Both citalopram total clearance and demethylation clearance (formation of desmethylcitalopram) were significantly lower in poor metabolizers of mephenytoin compared to extensive metabolizers (median 15.2 vs. 27.3 and 2.6 vs. 5.9 L/h, respectively). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the sparteine oxygenase CYP2D6. Didesmethylcitalopram could virtually not be detected in any poor metabolizers of sparteine, contrasting measurable serum levels in all sparteine/mephenytoin extensive metabolizers. The demethylation clearance of desmethylcitalopram was significantly lower in sparteine poor metabolizers compared to extensive metabolizers (0.3 vs. 2.4 L/h, respectively). During administration of citalopram, there was a modest increase in sparteine metabolic ratio from median 0.31 to 0.80 in extensive metabolizers of sparteine, whereas the mephenytoin S/R ratio was unaltered during citalopram treatment. Both the sparteine and the mephenytoin oxidation polymorphism thus appear to contribute partially to the total pharmacokinetic variability of citalopram.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8451774&dopt=Abstract citalopram Celexa



citalopram Celexa
Citalopram: interaction studies with levomepromazine, imipramine, and lithium.

Gram LF, Hansen MG, Sindrup SH, Brosen K, Poulsen JH, Aaes-Jorgensen T, Overo KF.

Department of Clinical Pharmacology, Odense University, Denmark.

The pharmacokinetic interactions between the selective serotonin reuptake inhibitor citalopram, given as an oral dose of 40 mg/day for 10 days, and (1) levomepromazine (50 mg single oral dose), (2) imipramine (100 mg single oral dose), and (3) lithium (30 mmol/day orally for 5 days) were examined in three panels each of 8 healthy young male volunteers (age 20-31). All volunteers were classified as extensive metabolizers of sparteine and mephenytoin. Each subject completed three study phases--one with citalopram alone, one with one of the three other drugs, alone, and one with citalopram combined with the corresponding other drug. For citalopram and its metabolites, a non-enantioselective analytical method (high-performance liquid chromatography) was used. Only two statistically significant interactions were indicated. First, levomepromazine caused a 10-20% increase from the initial steady-state levels of the primary citalopram metabolite, desmethylcitalopram. Second, citalopram caused approximately 50% increase in the single-dose area under the serum concentration/time curve of desipramine (primary metabolite or imipramine) and a corresponding reduction in the level of the subsequently formed metabolite 2-hydroxydesipramine. These findings are in agreement with the recent observations that (1) the demethylation of desmethylcitalopram (to didesmethylcytalopram) is partly mediated via the sparteine/debrisoquine oxygenase (CYP2D6) and that levomepromazine is a potent inhibitor of CYP2D6, and (2) that desmethylcitalopram has a somewhat stronger affinity for CYP2D6 than desipramine, and therefore may inhibit the hydroxylation of desipramine, which is also a substrate of CYP2D6.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8451775&dopt=Abstract citalopram Celexa



citalopram Celexa
Effects of citalopram, a synthetic serotonin uptake inhibitor, on indoleamine and catecholamine concentrations in the cerebrospinal fluid of freely moving rats.

Tohgi H, Abe T, Nakanishi M, Takahashi S, Furuichi H, Matsumura T, Kurimoto T, Izumi J, Ikeda Y.

Department of Neurology, Iwate Medical University, Morioka, Japan.

We studied changes in the concentrations of 5-hydroxytryptamine (5-HT), other indoleamines, and catecholamines in the cerebrospinal fluid (CSF) of freely-moving rats that had been administered citalopram, +/-1-[3- (Dimethylamino)propyl)-1-(4-fluorophenyl)-1, 3-dihydro-5-isobenzo-furancarbonitrile hydrobromide), a selective inhibitor of 5-HT uptake. In a microdialysis experiment, the intracerebral extracellular free 5-HT increased significantly, peaking 60 to 90 min after citalopram (30 mg/kg p.o.) was administered. The 5-HT concentrations in CSF from the cisterna magna increased significantly, reaching a maximum 6 hours after a single dose of citalopram (30 mg/kg p.o.) was given. Six hours after this dose, the CSF 5-HT concentration in the cisterna magna was significantly increased, and the 5-hydroxyindoleacetic acid (5-HIAA) concentration was significantly decreased. There were non-significant changes in the other indoleamines (tryptophan, 5-hydroxytryptophan, and kynurenine) and in the catecholamines (dopamine, homovanillic acid, normetanephrine, and 3-methoxy-4-hydroxyphenethyleneglycol). The 5-HT/tryptophan ratio was correlated significantly with the kynurenine/tryptophan ratio before treatment with citalopram (r = 0.81, p = 0.051), indicative that there is coordination of the serotonin and kynurenine pathways in normal rats. In the animals posttreatment there was no such correlation, suggesting that the changes in 5-HT are independent of the kynurenine system at least within the 6 hours postreatment. These CSF results appear to reflect selective inhibition of 5-HT uptake in brain tissues by citalopram that is not associated with changes in catecholamines.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8526996&dopt=Abstract citalopram Celexa